A-M. Vandamme et al. (Antiviral Chemistry & Chemotherapy, 1998 9:187-203) disclose current HAART clinical treatments of HIV-1 infections in man including at least triple drug combinations. Highly active anti-retroviral therapy (HAART) has traditionally consisted of combination therapy with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). These compounds inhibit biochemical processes required for viral replication. In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. While HAART has dramatically altered the prognosis for HIV infected persons, there remain many drawbacks to the current therapy including highly complex dosing regimes and side effects which can be very severe (A. Carr and D. A. Cooper, Lancet 2000 356(9239):1423-1430). Moreover, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance, thus limiting their utility in long term therapy. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
Compounds of the present invention modulate the activity of the chemokine CCR5 receptors. The chemokines are a large family of pro-inflammatory peptides that exert their pharmacological effect through G-protein-coupled receptors. The name “chemokine”, is a contraction of “chemotactic cytokines”. The chemokines are a family of leukocyte chemotactic proteins capable of attracting leukocytes to various tissues, which is an essential response to inflammation and infection. Human chemokines include approximately 50 small proteins of 50-120 amino acids that are structurally homologous. (M. Baggiolini et al., Annu. Rev. Immunol. 1997 15:675-705)
Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV-1 and genetically related retroviruses. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases. The chemokine receptor CCR5 is of particular importance in the context of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MWP) designated MIP-1a and MIP-1b, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).
HIV-1 infects cells of the monocyte-macrophage lineage and helper T-cell lymphocytes by exploiting a high affinity interaction of the viral enveloped glycoprotein (Env) with the CD-4 antigen. The CD-4 antigen, however appeared to be a necessary, but not sufficient requirement for cell entry and at least one other surface protein was required to infect the cells (E. A. Berger et al., Ann. Rev. Immunol. 1999 17:657-700). Two chemokine receptors, either the CCR5 or the CXCR4 receptor were subsequently found to be co-receptors along with CD4 which are required for infection of cells by the human immunodeficiency virus (HIV). The central role of CCR5 in the pathogenesis of HIV was inferred by epidemiological identification of powerful disease modifying effects of the naturally occurring null allele CCR5 Δ32. The Δ32 mutation has a 32-basepair deletion in the CCR5 gene resulting in a truncated protein designated Δ32. Relative to the general population, Δ32/Δ32 homozygotes are significantly common in exposed/uninfected individuals suggesting the role of CCR5 in HIV cell entry (R. Liu et al., Cell 1996 86(3):367-377; M. Samson et al., Nature 1996 382(6593):722-725).
The HIV-1 envelope protein is comprised of two subunits: gp120, the surface subunit and gp41, the transmembrane subunit. The two subunits are non-covalently associated and form homotrimers which compose the HIV envelope. Each gp41 subunit contains two helical heptad repeat regions, HR1 and HR2 and a hydrophobic fusion region on the C-terminus.
The CD-4 binding site on the gp120 of HIV appears to interact with the CD4 molecule on the cell surface that induces a conformation change in gp120 which creates or exposes a cryptic CCR5 (or CXCR-4) binding site, and undergoes conformational changes which permits binding of gp120 to the CCR5 and/or CXCR-4 cell-surface receptor. The bivalent interaction brings the virus membrane into close proximity with the target cell membrane and the hydrophobic fusion region can insert into the target cell membrane. A conformation change in gp41 allows the contact between the outer leaflet of the target cell membrane and the viral membrane which produces a fusion pore whereby the virus RNA is injected into the cytoplasm. Accordingly, an agent which could inhibit binding between gp120 and chemokine receptors should prevent or moderate infection in healthy individuals and slow or halt viral progression in infected patients. (B. Tomkowicz and R. G. Collman, Expert Opin. Ther. Targets 2004 8(2):65-78; J. P. Moore and R. W. Doms, Proc. Nat. Acad. Sci. USA, 2003 100(19):10598-10602)
Viral fusion and cell entry is a complex multi-step process and each step affords the potential for therapeutic intervention. These steps include (i) CD-40-gp120 interactions, (ii) CCR5 and/or CXCR-4 interactions and (iii) gp41 mediated membrane fusion. Each of these steps affords an opportunity for therapeutic intervention in preventing or slowing HIV infection
RANTES, a natural ligand for the CCR5 receptor, and an analog chemically modified on the N-terminus, aminooxypentane RANTES, were found to block HIV entry into the cells. (G. Simmons et al., Science 1997 276:276-279). Other compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science 1987 238:1704-1707), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gp120, the coat protein of HIV, to its target, the CD4 glycoprotein of the cell.
T20 (Entuvirtide) is a 36 amino acid peptide corresponding to residues 643-678 in the HR2 domain of gp41. T-20 binds a transient intermediate formed interaction after interaction of gp120 and the target cell which inhibits viral fusion thereby suppressing viral replication. (J. M. Kilby et al., New Eng. J. med. 1998 4(11):1302-1307). T-20 has been approved for clinical use.
In addition to the potential for CCR5 modulators in the management of HIV infections, the CCR5 receptor is an important regulator of immune function and compounds of the present invention may prove valuable in the treatment of disorders of the immune system. Treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis by administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of the present invention is also possible.
The pharmacokinetic challenges associated with large molecules, proteins and peptides resulted in the establishment of programs to identify low molecular weight antagonists of CCR5. The efforts to identify chemokine modulators have been reviewed (W. Kazmierski et al. Biorg Med. Chem. 2003 11:2663-76; L. Agrawal and G. Alkhatib, Expert Opin. Ther. Targets 2001 5(3):303-326; Chemokine CCR5 antagonists incorporating 4-aminopiperidine scaffold, Expert Opin. Ther. Patents 2003 13(9):1469-1473; M. A. Cascieri and M. S. Springer, Curr. Opin. Chem. Biol. 2000 4:420-426, and references cited therein)
Takeda's program was the first to lead to fruition with the identification of TAK-779 (M. Shiraishi et al., J. Med. Chem. 2000 43(10):2049-2063). Schering has advanced Sch-351125 into Phase I/II clinical studies and reported the advance of a more potent follow-up compound, Sch-417690 into Phase I studies. (S. W. McCrombie et al., WO00066559; B. M. Baroudy et al. WO00066558; A. Palani et al., J. Med Chem. 2001 44(21):3339-3342; J. R. Tagat et al., J. Med Chem. 2001 44(21):3343-3346; J. A. Esté, Cur. Opin. Invest. Drugs 2002 3(3):379-383).

Merck has disclosed the preparation of (2S)-2-(3-chlorophenyl)-1-N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzothiophene-3,4′-piperidin-1′-yl)butane S-oxide (1) and related derivatives, trisubstituted pyrrolidines 2 and substituted piperidines 3 with good affinity for the CCR5 receptor and potent-HIV activity. (P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:265-270; P. E. Finke et al., Bioorg Med. Chem. Lett., 2001 11:2469-2475; P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:2475-2479; J. J. Hale et al., Bioorg. Med. Chem. Lett., 2001 11:2741-22745; D. Kim et al., Bioorg. Med. Chem. Lett., 2001 11:3099-3102)

WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.) disclose heterocyclic compounds that are potent and selective CCR5 antagonists. UK-427857 has advanced to clinical trials and show activity against HIV-1 isolates and laboratory strains (M. J. Macartney et al., 43rd Intersci. Conf. Antimicrob. Agents Chemother. (Sep. 14-17, 2003, Abstract H-875).

Due to their rigidity and the ease of functionalization, bicyclic and tricyclic amines have proven to be useful scaffolds in drug design. Compounds based upon the 3,7-diazabicyclo[3.3.0]octane (4: R′═R″═H) are known for use in a variety of medical applications, including inter alia as migraine (as described in WO 98/06725 and WO97/11945); antibiotics (as described in WO 97/10223 and WO 96/25691, neuroleptics (as described in WO 95/15327 and WO95/13279); serotonin reuptake inhibitors (as described in WO 96/07656); thrombin inhibitors (as described in Helv. Chim. Acta 2000 83:855, Chem. & Biol. 1997 4:287 and Angew. Chem. Int. Ed. Eng 1995 34:1739); and, anxiolytic agents (J. Med. Chem. 1989 32:1024). In addition, compounds based upon 3,7-diazabicyclo[3.3.0]octane have been used in the treatment of gastrointestinal disorders (DE 39 30 266 A1) disorders of the glutaminergic system. WO 00/55143 discloses diamine compounds, including 3,7-diazabicyclo[3.3.0]octane compounds linked to an oxazolone which compounds are α-1 adrenoreceptor modulators. EP 1 122 257 (F. Ito et al.) disclose benzimidazole compounds linked to a variety bicyclic diamine compounds including diazabicyclooctanes which compounds are ORL-1 receptor agonists. The ORL-1 receptor is an opioid receptor subtype.
WO 96/07656 (J. M. Schaus and R. D. Titus) disclosed aralkyl substituted 3,7-diazabicyclo[3.3.0]octane compounds with selective reuptake inhibitory activity. WO 97/11945 (A. Madin) disclose 3-substituted 3,7-diazabicyclo[3.3.0]octane compounds, which may be further substituted at the 7-position, with selective 5-HTIDα activity. WO 01/44243 (D. Peters et al.) disclose novel heteroaryl 3-substituted-diazabicycloalkane compounds, which may be optionally substituted at the 7-position, which are muscarinic and nicotinic receptor modulators which are useful in the treating diseases associated with degeneration of the cholinergic system. The preferred embodiments include 3,7-diazabicyclo[3.3.0]octane compounds 4 wherein R′ is a heteroaryl group and R″ is hydrogen, alkyl, aryl, aralkyl or a fluorescent group.
WO 02/07523 A1 (R. Colon-Cruz et al.) discloses 3,7-diazabicyclo[3.3.0]octane compounds which are antagonists of the chemokine CCR2 and CCR3 receptors. MCP-1 is believed the natural ligand for the CCR2 receptor and interaction of the ligand with the receptor increases histamine release, calcium influx, cAMP activation, increases integrin expression and acts as a chemotactic factor for monocytes and macrophages. Compounds disclosed in the invention were claimed useful for the treatment of diseases of monocyte, lymphocyte and leukocyte accumulation and more specifically atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, Crohn's disease, encephalomyelitis and transplant rejection. The preferred embodiments include compounds with the generic formula 5.

WO 02/060902 A1 (M. Björsne et al.) disclose 3,7-diazabicyclo[3.3.0]octane compounds useful in the treatment of cardiac arrhythmias. The preferred embodiments include compounds with the generic formula 6.
